Aim To evaluate the long-term effects of lipoprotein (a) [Lp(a)] on the development of coronary atherosclerosis in Wahanabe heritable hyperlipidemic (WHHL) rabbits, to further study the mechanism of Lp(a) in the process of atherosclerosis. Methods Generated human apolipoprotein (a) [apo(a)] transgenic (Tg) WHHL rabbits were compared with non-Tg WHHL rabbits aged 24 months (fed a standard chow diet). Plasma levels of Lp (a), total cholesterol (TC), triglyceride (TG), high density lipoproteins cholosterol (HDLC) and plasma levels of C-reactive protein (CRP) were measured using the methods. Area of intimal lesion and stenosis degree were measured by histologically staining and the components in the lesions were analyzed using immunohistochemical staining. Result The mean levels of human Lp(a) in Tg rabbit plasma were 9.1±3.5 nmol/L at 24 months. Compared to non-Tg WHHL rabbits, Tg WHHL rabbits did not show significant changes in plasma TC, TG, or HDLC. However, Tg WHHL rabbits showed 3.5-fold increased lesions in right coronary arteries than non-Tg WHHL rabbits (P<0.05). Increased lesion size in RCA of Tg WHHL rabbits did not result in a proportional increase of lumen stenosis in RCA (26.9±6.6% in non-Tg vs 27.7±5.0% in Tg), suggesting that compensational remodeling occurred as the diameter of RCA of Tg WHHL rabbits were markedly increased (1.8±0.6 mm2 in non-Tg vs 5.3±1.1 mm2 in Tg, P<0.05). Human apo (a) immuno-reactive proteins were focally present in the lesions of Tg WHHL rabbits and associated with apolipoprotein B, but mainly located around the extracellular matrix rather than associated with macrophages. Cellular components accounted for less than 10% of the lesions and there were no difference between non-Tg and Tg WHHL rabbits. Three Tg rabbits (33%) and one non-Tg WHHL rabbits (9%) which had apparently extensive myocardial infarction lesions were detected. Conclusion Increased plasma levels of Lp (a) enhance the coronary atherosclerosis in the setting of hypercholesterolemia.